Cross-linked Hyaluronic Acid and Coenzyme Q10 in the Treatment of Dry Eye

Dry Eye Syndrome Clinical Trial

— DEDCO  

Official title:

Study on the Effectiveness of Eye-drops Containing Cross-linked Hyaluronic Acid and Coenzyme Q10 in the Treatment of Patients With Mild to Moderate Dry Eye

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03074344
• Other study ID #: AOUGMartino
• Status: Completed
• Phase: N/A
• First received: February 28, 2017
• Last updated: March 8, 2017
• Start date: May 2016
• Est. completion date: November 2016

Study information

• Verified date: March 2017
• Source: Azienda Ospedaliera Universitaria Policlinico "G. Martino"
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Background: Dry eye disease (DED) is a common condition causing burden on visual function and reducing quality of life. Corticosteroids and/or cyclosporine eye drops are able to improve DED symptoms, however, side effects of immune suppression and cost lead patients often to suspend treatment. Consequently, is important to identify therapies alleviating DED symptoms. A randomized, controlled, single masked study, was performed in 40 patients affected by mild to moderate DED, to evaluate efficacy and safety of a collyrium based on cross-linked hyaluronic acid (XLHA) added with Coenzyme Q10 (CoQ10) in comparison to an eye drop considered a gold standard for tear substitutes, based on hyaluronic acid (HA) 0.15%.

Methods: eye drops were administered four times a day for 90 days to enrolled subjects divided in two groups: group A treated with XLHA+CoQ10, group B treated with HA. Ocular Surface Disease Index (OSDI) questionnaire, visual acuity, intraocular pressure (IOP), fundus exam, tear break-up time (TBUT), corneal and conjunctival fluorescein staining, corneal esthesiometry, corneal confocal microscopy, were performed at different visits until the 90th day.

Description:

Introduction:

Dry eye disease (DED) is a common eye condition causing burden on visual function and reducing quality of life and work productivity. DED is a tear film disorder resulting in hyperosmolarity of tear film and inflammation of ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. This condition provokes traumatisms caused by the movement of the eyelids on the ocular surface and an insufficient cleansing of the same by microbial agents and/or foreign bodies.

Prevalence of DED increases with age and women are particularly susceptible, especially those receiving estrogens. The pathogenesis is not fully understood; however, it has been recognized that inflammation has a prominent role .

The most common symptoms of DED are: burning, foreign body sensation in the eye, difficulty in opening the eyelids on awakening, blurred vision and, in severe cases, pain and photophobia. DED is accompanied by increased tear film osmolarity and inflammation of ocular surface.

There is no gold standard treatment for DED, but corticosteroids and/or cyclosporine eye drops improve the symptoms. However, given the side effects of immune suppression and the cost of pharmaceutical preparations, patients often suspend treatment before the effectiveness of therapy can be verified.

Artificial tears are considered a mainstay in dry eye treatment. Hyaluronic acid (HA), a natural glycosaminoglycan, is a component of tear film. It increases tear film viscosity and hydrates and lubricates the ocular surface. HA possesses intrinsic water retention properties, viscoelasticity and favours the healing of corneal and conjunctival epithelium. Safety and efficacy of HA for the treatment of DED has been demonstrated. Eye-drops containing HA determine a reduction of ocular surface inflammation, with consequent improvement of quality of corneal and conjunctival epithelium. Our previous clinical study showed HA beneficial effects on the conjunctival epithelium of dry eye patients. Results of another clinical trial, confirm beneficial effects of HA and show that in combination with tamarind seed polysaccharide it can be effective in improving dry eye symptoms, opening new scenarios in the treatment of this disease by combining different molecules.

Coenzyme Q10 (CoQ10) is an endogenous, lipid soluble molecule, also known as ubiquinone. CoQ10 plays a key role in oxidative metabolism supporting the adenosine triphosphate (ATP) in the mitochondria and, in its reduced form, acts as a lipid antioxidant. In almost all tissues of the human body, CoQ10 levels decline with age and ocular function is sensitive to variations of concentration of CoQ10 .

A randomized, controlled, single masked study, was performed in mild to moderate dry eye patients, to evaluate the efficacy and the safety of a collyrium based on cross-linked HA (XLHA) added with CoQ10 in comparison to an eye drop formulation, commonly used in clinical practice and considered a gold standard for tear substitutes, in the treatment of dry eye, based on 0.15% linear HA.

Methods This randomised, single-masked, parallel-group comparative study investigated the efficacy and safety, in treatment of dry eye patients, of an ophthalmic solution containing XLHA added with CoQ10 (VisuXL®, Visufarma, Rome, Italy) in comparison with a formulation containing hyaluronic acid 0.15% (HA). The study screened 46 patients and 40 were enrolled [(13 male, 17 female, with an age range 40-79 years; mean age 62 ± 12.8 (SD) years)] suffering from mild to moderate dry eye attending to the Eye Clinic, Department of Biomedical Sciences, Regional Referral Center for the Ocular Surface Diseases, University of Messina, Messina, Italy. Enrolled subjects were divided into two treatment groups (Group A receiving the study formulation based on XLHA+CoQ10 and Group B receiving the comparator formulation based on 0.15% HA) according to a randomization scheme, corresponding to allocation codes generated for the two treatments using the permuted block method. The two eye-drops compositions used for the study were the following: group A formulation (XLHA+CoQ10): 100 ml containing Cross-Linked HA sodium salt 100 mg, Coenzyme Q10 100 mg, with Vitamin E tocopheryl polyethylene glycol succinate (TPGS) 500 mg (as a solubilizing agent for the lipid soluble CoQ10), Isotonic buffered solution q.s. to 100 ml; group B formulation: HA sodium salt 100 mg; isotonic buffered solution q.s. to 100 ml. Both formulations were unpreserved.

All patients included were treated for a run-in period of 7 days with one eye drop of saline four times daily. At the end of this period (time 0 of the study) the subjects were randomly divided into the two groups and assigned to a treatment.

The visits were carried out in a blind fashion by investigators. Eye drops were administered four times a day for 12 weeks and subjects enrolled in the study underwent grading of subjective symptoms and clinical examination at time 0 and after 15, 30, and 90 days. The patients were allowed to know the brand name of the eye drops they were using.

Outcomes The Ocular Surface Disease Index (OSDI) questionnaire, visual acuity, intraocular pressure (IOP), and fundus exam, tear break-up time (TBUT), corneal and conjunctival fluorescein staining, esthesiometry, corneal confocal microscopy. Adverse events were monitored.

OSDI is one of the most widely used questionnaires. The 12-item OSDI questionnaire scores range from 0 to 100, high scores represent higher disability. The scale showed good sensitivity in discriminating normal people from subjects affected by dry eye and to correlate well with disease severity.

The ocular surface fluorescein stain score was assessed 3 minutes after the instillation of fluorescein; a modified Oxford score was used: cornea and conjunctiva were scored separately from 0 to 5 (from 0 = none to 5 = extended areas of confluent stain), for the conjunctiva a mean for the scores from the nasal and temporal regions was used. The ocular surface was observed through a cobalt blue light and a Wratten #12 yellow filter.The difference among the scores obtained in each visit was calculated.

Corneal sensitivity was measured by Cochet-Bonnet aesthesiometer to evaluate the activity of the ophthalmic branch of fifth cranial nerve (trigeminal). It was measured by the evaluating the length of the filament able to evoke a tactile sensation (mm of filament).

In vivo confocal microscopy was performed, after the topical instillation of a drop of unpreserved 0.4% oxybuprocaine, using the 40x contact objective and the additional Z-Ring probe, to allow a precise positioning of the probe over the central corneal area.

For statistical analysis, only the results of right eyes were considered. Student's t-test and Mann-Whitney U-test were used as appropriate. Values of P≤0.05 were considered statistically significant.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: November 2016
• Est. primary completion date: July 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 40 Years to 80 Years

Eligibility

Inclusion Criteria:

• age between 18 and 80 years,

• history of at least 3 months of dry eye symptoms referable to mild to moderate dry eye.

Exclusion Criteria:

• presence of any ocular disease, present or past, other than dry eye;

• previous ocular surgery,

• use of contact lens or topic treatments other than tear substitutes;

• presence of systemic diseases requiring a treatment with systemic drugs potentially interfering with tear productions;

• hypersensitivity to the active substance or to excipients;

• participation in a clinical trial during the 3 months prior to the beginning of the study,

• pregnancy or breast-feeding.

Related Conditions & MeSH terms

• Dry Eye Syndrome
• Dry Eye Syndromes
• Keratoconjunctivitis Sicca

Intervention

Device:
• XLHA+CoQ10
XLHA+CoQ10 for four times a day for 12 weeks.
• Hyaluronic acid (HA)
Hyaluronic acid (HA) for four times a day for 12 weeks.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Azienda Ospedaliera Universitaria Policlinico "G. Martino"

References & Publications (19)

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Aragona P, Papa V, Micali A, Santocono M, Milazzo G. Long term treatment with sodium hyaluronate-containing artificial tears reduces ocular surface damage in patients with dry eye. Br J Ophthalmol. 2002 Feb;86(2):181-4. — View Citation

Barabino S, Rolando M, Nardi M, Bonini S, Aragona P, Traverso CE. The effect of an artificial tear combining hyaluronic acid and tamarind seeds polysaccharide in patients with moderate dry eye syndrome: a new treatment for dry eye. Eur J Ophthalmol. 2014 — View Citation

Baudouin C, Aragona P, Van Setten G, Rolando M, Irkeç M, Benítez del Castillo J, Geerling G, Labetoulle M, Bonini S; ODISSEY European Consensus Group members.. Diagnosing the severity of dry eye: a clear and practical algorithm. Br J Ophthalmol. 2014 Sep;98(9):1168-76. doi: 10.1136/bjophthalmol-2013-304619. — View Citation

Benítez-Del-Castillo J, Labetoulle M, Baudouin C, Rolando M, Akova YA, Aragona P, Geerling G, Merayo-Lloves J, Messmer EM, Boboridis K. Visual acuity and quality of life in dry eye disease: Proceedings of the OCEAN group meeting. Ocul Surf. 2016 Nov 29. pii: S1542-0124(16)30234-8. doi: 10.1016/j.jtos.2016.11.003. [Epub ahead of print] — View Citation

Fabiani C, Barabino S, Rashid S, Dana MR. Corneal epithelial proliferation and thickness in a mouse model of dry eye. Exp Eye Res. 2009 Aug;89(2):166-71. doi: 10.1016/j.exer.2009.03.003. — View Citation

Faulkner WJ, Varley GA. Corneal diagnostic techniques. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. 2nd ed. Vol. 1 Philadelphia: Elsevier/Mosby; 2005:229-235.

Fernandez MM, Afshari NA. Nutrition and the prevention of cataracts. Curr Opin Ophthalmol. 2008 Jan;19(1):66-70. Review. — View Citation

Frei B, Kim MC, Ames BN. Ubiquinol-10 is an effective lipid-soluble antioxidant at physiological concentrations. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4879-83. — View Citation

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Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among US women. Am J Ophthalmol. 2003 Aug;136(2):318-26. — View Citation

Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of the Ocular Surface Disease Index. Arch Ophthalmol. 2000 May;118(5):615-21. — View Citation

She Y, Li J, Xiao B, Lu H, Liu H, Simmons PA, Vehige JG, Chen W. Evaluation of a Novel Artificial Tear in the Prevention and Treatment of Dry Eye in an Animal Model. J Ocul Pharmacol Ther. 2015 Nov;31(9):525-30. doi: 10.1089/jop.2015.0042. — View Citation

Stevenson W, Chauhan SK, Dana R. Dry eye disease: an immune-mediated ocular surface disorder. Arch Ophthalmol. 2012 Jan;130(1):90-100. doi: 10.1001/archophthalmol.2011.364. Review. — View Citation

Stocker R, Bowry VW, Frei B. Ubiquinol-10 protects human low density lipoprotein more efficiently against lipid peroxidation than does alpha-tocopherol. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1646-50. — View Citation

Sullivan BD, Whitmer D, Nichols KK, Tomlinson A, Foulks GN, Geerling G, Pepose JS, Kosheleff V, Porreco A, Lemp MA. An objective approach to dry eye disease severity. Invest Ophthalmol Vis Sci. 2010 Dec;51(12):6125-30. doi: 10.1167/iovs.10-5390. — View Citation

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* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Ocular Surface Disease Index (OSDI) questionnaire.	The OSDI is assessed on a scale of 0 to 100, with higher scores representing greater disability. OSDI is a valid and reliable instrument for measuring dry eye disease (normal, mild to moderate, and severe) and effect on vision-related function. OSDI demonstrates sensitivity and specificity in distinguishing between normal subjects and patients with dry eye disease.	Up to 90 days.
Primary	Corneal and conjunctival staining.	Corneal and conjunctival staining of the ocular surface after instillation of vital dyes was developed to quantify epithelial surface damage in dry eye patients. Ocular surface fluorescein stain score was assessed 3 minutes after the instillation of fluorescein; a modified Oxford score was used: cornea and conjunctiva were scored separately from 0 to 5 (from 0 = none to 5 = extended areas of confluent stain), for the conjunctiva a mean for the scores from the nasal and temporal regions was used. The ocular surface was observed through a cobalt blue light and a Wratten #12 yellow filter.The difference among the scores obtained in each visit was calculated.	Up to 90 days.
Secondary	Visual acuity,	Visual acuity refers to the ability to discern fine distinctions in the environment.	Up to 90 days.
Secondary	Intraocular pressure (IOP).	IOP = eye fluid pressure measured by tonometry.	Up to 90 days.
Secondary	Fundus exam.	Fundus exam is observed after use of mydriatic drops enlarging the pupil.	Up to 90 days.
Secondary	Tear break-up time (TBUT).	Tear breakup time (TBUT) is a test used to assess for evaporative dry eye disease. To measure TBUT, fluorescein is instilled into the patient's tear film then and the patient is asked not to blink while the tear film is observed under cobalt blue illumination. TBUT is recorded as the number of seconds that elapse between the last blink and the appearance of the first dry spot in the tear film, as seen in this progression of these slit lamps photos over time. A TBUT under 10 seconds is considered abnormal.	Up to 90 days.
Secondary	Corneal esthesiometry.	Esthesiometry measures sensation, specifically tactile.	Up to 90 days.